The goal for this renewal application is to a) elucidate oncogenic Kras (Kras*)-regulated metabolic pathways mediating pancreatic ductal adenocarcinoma (PDAC) tumor maintenance, b) define collateral metabolic dependencies, and c) establish how interventions targeting these processes influence tumor immunity, in order to guide the design of clinical trials with existing drugs and to identify new therapeutic points of attack. Our P01 program comprises 3 highly interdependent and collaborative projects and 4 essential cores with the goals of conquering PDAC through targeting metabolic vulnerabilities in conjunction with immunotherapy. Project 1 has demonstrated that Kras* extinction in PDAC leads to pronounced tumor regression that involves critical functions of Kras* in metabolic reprogramming. We have also identified Kras*-extinction resistant cells (KRCs), which show dramatic adaptive metabolic changes (in OXPHOS and autophagy) allowing survival upon Kras* inactivation. These studies thereby provide benchmarks for successfully targeting Kras* in vivo and predicting resistance mechanisms that may be encountered in the clinic. Thus, the goal of Project 1 is to kill the bulk Kras*-dependent tumor cells through identification of metabolic targets essential for Kras*-mediated PDAC maintenance and to define methods to eliminate KRC through inhibiting autophagy and OXPHOS survival mechanisms. Project 2 has discovered that PDAC is dependent on lysosome-dependent nutrient scavenging pathways for metabolic homeostasis and tumor growth, and has identified a transcriptional program that activates these processes. The goal of Project 2 is to decipher how lysosomal scavenging supports PDAC growth and how cancer cells can escape their dependence on these processes, thereby informing improved therapeutic approaches. Project 2 will identify the metabolic outputs of lysosomal mediated recycling pathways, establish which of these outputs play roles in PDAC growth, and explore metabolic escape pathways in order to identify novel therapeutic combinations synergizing with lysosomal inhibition. Project 3 has defined profound alterations in the tumor microenvironment, including a prominent CD8 T cell infiltration following Kras* extinction in PDAC. Project 3 will define the immune profiles throughout the genesis, regression and recurrence of PDAC and will determine the causal role of CD8 and CD4 cells in PDAC regression, as well as explore new opportunities to test the efficacy of checkpoint blockade therapy and assess the associated adaptive mechanisms underlying immune suppression. Furthermore, Project 3 will determine the direct impact of metabolically targeted therapy on tumor immunity and define effective methods to combine such therapies with immune checkpoint blockade therapy. Highly innovative cores for Pathology, Preclinical Therapeutics, Computation, and an Administrative Core will enable these Projects.